School of Infection & Immunity

Study Summary (including aims, timelines and funder):

Psoriatic arthritis (PsA) and psoriasis are characterised by immune, metabolic, and vascular dysfunction. There is an increase in Major Adverse Cardiovascular Events in PsA and psoriasis not explained by conventional cardiovascular risk factors. Further, obesity is strongly associated with psoriasis and PsA. Dietary interventions leading to weight loss are associated with improvement in disease activity. Phosphodiesterase 4 (PDE4) inhibition with apremilast, licensed for treatment of PsA and psoriasis, has been noted to be associated with weight loss. PDE4 may help explain the link between immune and cardiometabolic dysfunction characterising PsA and psoriasis, with pathogenic and therapeutic implications.

This study aims to use apremilast as a clinical molecular probe to evaluate the effects of PDE4 inhibition on metabolic, vascular, and immune status in patients with PsA and psoriasis. 

Measurement of metabolic, immunological and vascular outcomes in 60 patients with PsA and/or psoriasis receiving apremilast as part of their standard clinical care will be taken. A subgroup of participants with PsA will also undergo more in-depth investigations including MRI of abdominal fat distribution, subcutaneous adipose tissue biopsy, vascular endothelial function, and more detailed immunophenotyping. Participants will be recruited from rheumatology and dermatology clinics in NHS Greater Glasgow and Clyde (primary site), as well as from NHS Lanarkshire and NHS Highland.

This is an investigator-initiated study funded by Celgene, manufacturer of apremilast, with sub-study funding from the BHF Centre of Research Excellence. Celgene do not supply or fund apremilast, this is prescribed as part of standard clinical care.

Study Summary (including aims, timelines and funder):

Part of the MATURA consortium led by Queen Mary University London, the Stratification of Biologic Therapies for RA by Pathobiology (STRAP) study is investigating 3 biological therapies; Rituximab, Tocilizumab and Etanercept. The study started in November 2015 and is investigating whether the most effective drug for a specific patient can be identified by examining the joint tissue from synovial biopsies. 

The aim of this study is to investigate whether the most effective choice of biologic medicine for people with RA may be guided by examining the joint tissue (synovial tissue) and, in particular, whether different levels of immune cells (called B cells) within the joint can predict response to treatment.

The ultimate aim is to provide a tailored approach to treatment decisions for people with RA, in order to maximize their potential response to biologic medicines. 

Who can participate? (Inclusion/exclusion criteria)

Patients with active (DAS28 ≥ 5.1) who have failed at least 2 Disease Modifying Anti-Rheumatic Drugs (or DMARDs; including methotrexate, sulfasalazine and hydroxychloroquine), who have not previously received treatment with biologic drugs.

Glasgow started recruitment in October 2016.  11 patients have been recruited in Glasgow to date.  

What does the study involve?

With your permission, you will first attend a screening visit (approximately 1 hour), which will assess your eligibility for the study in more detail, which will include:

• Full medical history including medical conditions and surgical procedures, allergies, medication list, etc 
• Completing questionnaires
• A full physical examination 
• Thorough examination of all your joints
• Chest X-ray
• Electrocardiography (ECG)
• Routine blood test
• Vital signs including blood pressure, pulse rate, 
• Urine pregnancy test if you are a woman of child-bearing age

If the tests show that you are suitable for the study and you agree to take part, you will need to agree to have a biopsy of one of your inflamed joints (usually the knee or wrist joint). This will be done by a doctor and will involve removal of small tissue samples from the lining of the joint (synovial tissue). Following this, you will be assigned to one of three treatments (etanercept, rituximab or tocilizumab), which you will first receive on the ‘baseline’ visit.  Subsequently, you will attend follow-up visits every 4 weeks for a total of 24 weeks. During these visits, you will be asked to complete questionnaires and have some tests carried out. 

 These tests may include:

• Blood tests
• Additional biopsies (optional)
• X-rays of your hands and feet

Are there any benefits or risks associated with taking part in this study?

A perceived risk to the patient may be that of undergoing synovial biopsy.  Minimally invasive ultrasound-guided synovial biopsy has been practiced since 2007. This procedure was specifically developed to minimise discomfort and inconvenience for patients with newly developed arthritis and has been shown to be safe and well tolerated by patients, as well as generating high quality samples, including from patients in clinical remission. The three main units using this technique internationally (including Birmingham) have completed more than 1000 biopsies with no major adverse events. Audit of biopsies in Birmingham has demonstrated that >90% of patients experience nothing more than mild to moderate discomfort during the procedure, with >80% of patients likely to consent to a second biopsy.

We cannot predict the outcome of the study or participants individual responses to treatment.  The three therapies participants may receive in the study are routinely used in patients with RA by clinicians as usual clinical care.  They have all proven effective for the management of RA, but determining which drug is best for which patient is ultimately what the trial aims to discover; hence, responses may vary within the study as they would in standard care.  An important benefit to participating is that patients will be monitored very closely by the clinical research team. They will have a dedicated research nurse who you will be able to contact directly with any questions or concerns relating to your care or participation throughout the study.  

 Additionally, although not of direct benefit, participation in this study will provide important new information about the feasibility and acceptability of approaches to preventing RA.

Study contacts for further information

Dr Seán Kerrigan, Glasgow Clinical Research Facility 0141 211 6800 or email: arthritisresearch@glasgow.ac.uk

Study Summary (including aims, timelines and funder):

ICoSRA is an international clinical study which utilises laboratory based, genetic patient screening and analysis to unravel immune responses in people with rheumatoid arthritis. The study aims to identify predictive markers of response to rheumatoid arthritis treatment regimes.  It also will provide new information about why the disease occurs and thereby point to future possible approaches to cure.

Rheumatoid arthritis (RA) is a chronic inflammatory immune-mediated arthritis which leads to pain, swelling and destruction of joints. RA affects more than 500,000 subjects in the UK and incurs significant health and economic cost. Most patients require potent immune suppressing drugs such as methotrexate, which help reduce pain and stiffness, and protect the joints against damage. However, many patients do not respond or are unable to tolerate methotrexate. In these patients, biologic drugs such as abatacept are used to try to control the arthritis.  

Abatacept is an injectable medicine designed to target and inhibit a specific molecule involved in “costimulation” of the inflammatory signal (that switches on white blood cells) that is thought to be important in RA. While abatacept has been shown to be effective in trials and clinical practice, the exact mechanism of action of abatacept in RA has not been fully elucidated. Understanding these actions is likely to inform both the use of abatacept in RA and lead to increased understanding of inflammation in humans with implications for further therapies. This six month prospective open-label study, therefore, aims to investigate the effects of inhibiting co-stimulation on a variety of important inflammatory cell types and processes in humans with RA.

This study is funded by Bristol-Myers Squibb.

Who can participate? (Inclusion/exclusion criteria)

25 participants with RA who have bad prognostic genetic markers (ACPA and HLA-DR4) and who were scheduled to receive subcutaneous abatacept as part of their standard clinical treatment will be recruited. 

 What does the study involve?

Consenting participants will be followed for a total of 24 weeks during which time they will have additional venous blood and urine samples taken to investigate the effects of abatacept on their immune cells and system. The primary endpoint of the study is the characterisation of the immune response following costimulatory modulation in RA patients at 12 weeks. Secondary endpoints include change in immunological response and its association with clinical outcome measures up to 24 weeks.

Are there any benefits or risks associated with taking part in this study?

We cannot predict the outcome of the study, but there is the possibility that there will be benefits to those subjects receiving the active drug, including reduction of joint symptoms and effects on the disease process that could delay or even prevent the onset of arthritis or RA.  Another important benefit to participating is that you will be monitored very closely by the clinical research team. You will have a dedicated research nurse who you will be able to contact directly with any questions or concerns relating to your care or participation throughout the study.  

Study Title: 

Scottish Early Rheumatoid Arthritis (SERA) biobank from an inception cohort of patients with newly diagnosed rheumatoid arthritis.

Study Summary (including aims, timelines and funder):

The Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of rheumatoid (RA) and undifferentiated arthritis (UA) patients that aims to provide a contemporary description of phenotype and outcome and facilitate discovery of phenotypic and prognostic biomarkers.  Originally funded by the Chief Scientist Office and Pfizer, SERA is now closed to recruitment.

Study Outcome:

SERA was a population-wide inception cohort that recruited new onset rheumatoid arthritis patients (RA n=1173; Healthy Volunteers n=100) in a routine NHS setting. Clinical characteristics including therapeutics and disease activity parameters were recorded with a broad range of biobanked biological samples (>65,000 samples e.g. DNA, RNA, serum, plasma, urine). 

Using the Community Health Index (CHI) number each participant is electronically linked to core NHS data services (Robertson Centre, Glasgow; Farr, Edinburgh) to track e.g. medical episodes, co-morbidities, death, community prescribing, in perpetuity.

In routine care, newly diagnosed RA/UA patients experience significant improvements in disease activity, functional ability and health-related quality of life but have high rates of multi-morbidity and declining employment rates. The co-existence of a multi-domain description of phenotype and a comprehensive biobank will facilitate multi-platform translational research to identify predictive markers of phenotype and prognosis.

GDPR Statement

The introduction of the GDPR regulations brings with it stricter requirements around how organisations inform people of how their personal data is being used for health and care research.

To meet this requirement the Health Research Authority (HRA) has issued guidance to those organisations to explain to you how we are using your personal data, and what your rights are under the law.

This information is outlined below and separate additional text has been published by the HRA on behalf of the NHS, to ensure that patients can find consistent transparency information.

• General Data Protection Regulations (GDPR) Notice

Publications:

• 2022

Frailty in rheumatoid arthritis and its relationship with disease activity, hospitalisation and mortality: a longitudinal analysis of the Scottish Early Rheumatoid Arthritis cohort and UK Biobank. RMD Open, 8(1), e002111. (doi: 10.1136/rmdopen-2021-002111) (PMID:35292529) (PMCID:PMC8928366

• 2021

Nijjar J, Morton FR, Bang H, Buckley CD, van der Heijde D , Gilmour A et al.   The impact of autoantibodies against citrullinated, carbamylated, and acetylated peptides on radiographic progression in patients with new-onset rheumatoid arthritis: an observational cohort study. The Lancet. Rheumatology, 27 Jan 2021, 3(4):e284-e293

• 2020

Fragoulis G et al, Depression and anxiety in an Early Rheumatoid Arthritis inception cohort. Associations with demographic, socioeconomic and disease features. RMD Open 2020;6:e001376. doi: 10.1136/rmdopen-2020-001376

• 2019

Gabrielle Simoneau, Erica E. M. Moodie, Jagtar S. Nijjar, Robert W. Platt & the Scottish Early Rheumatoid Arthritis Inception Cohort Investigators (2019) Estimating Optimal Dynamic Treatment Regimes With Survival Outcomes, Journal of the American Statistical Association, DOI: 10.1080/01621459.2019.1629939

• 2018

Carini, C., Hunter, E., Porter, D. et al. Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis. J Transl Med 16, 18 (2018) doi:10.1186/s12967-018-1387-9

Ann Morgan, John Taylor, Tim Bongartz, et al, Genome-wide Association Study of Response to Methotrexate in Early Rheumatoid Arthritis Patients. The Pharmacogenomics Journal 2018 http://doi.org/10.1038/s41397-018-0025-5

Fragoulis GE, Paterson C, Gilmour A, et al. Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome. RMD Open 2018;4:e000739. doi:10.1136/rmdopen-2018-000739

• 2017

Siebert, S. et al. Urinary proteomics can define distinct diagnostic inflammatory arthritis subgroups. Sci. Rep. 7, 40473; doi: 10.1038/srep40473 (2017).

• 2016

Kronisch C, McLernon DJ, Dale J, Paterson C, Ralston SH, Reid DM, et al. Brief report: predicting functional disability: one-year results from the scottish early rheumatoid arthritis inception cohort. Arthritis Rheumatol. 2016;68:1596–602.

Dale J, Paterson C, Tierney A, Ralston SH, Reid DM, Basu N, et al. The Scottish Early Rheumatoid Arthritis (SERA) Study: an inception cohort and biobank. BMC Musculoskelet Disord. 2016;17:461.

• 2014

Stalmach A, Johnsson H, McInnes IB, Husi H, Klein J, Dakna M, et al. (2014) Identification of Urinary Peptide Biomarkers Associated with Rheumatoid Arthritis. PLoS ONE 9(8): e104625. https://doi.org/10.1371/journal.pone.0104625

ACR abstracts:

E Clark, C Wood, A Tindell, K Graham, A McIntosh, F Morton and D Porter. Unmet need in early rheumatoid arthritis - why do some patients do badly despite modern treat-to-target strategies of care? Results from the Scottish Early RA (SERA) inception cohort. https://acrabstracts.org/abstract/unmet-need-in-early-rheumatoid-arthritis-why-do-some-patients-do-badly-despite-modern-treat-to-target-strategies-of-care-results-from-the-scottish-early-ra-sera-inception-cohort/

D Porter, F Morton, S Jain. Increase rates of bacterial infection in patients with 'pre-RA' (submitted 2022)

Study Title:     

Arthritis Prevention in the Pre-Clinical Phase of RA with Abatacept (APIPPRA)

Study Summary (including aims, timelines and funder):

The APIPPRA study is a UK wide 2-year study that aims to test whether medication already licensed for use in Rheumatoid Arthritis (RA) can prevent or delay the onset of the disease in those people at risk of developing RA.  The lead sponsor is King’s College London and the study is supported by the NIHR.

Before people develop RA they may begin to have joint pains and have antibodies associated with RA in their blood.  This trial is testing whether abatacept can help modulate the inflammatory system to prevent or delay the development of the full disease. 

Who can participate? (Inclusion/exclusion criteria)

This trial is now closed to recruitment but has follow-up ongoing.

Glasgow has recruited 11 patients. The first patient was recruited in December 2015 and the last in January 2019. 

What does the study involve?

The study is designed as a randomised, double blind, placebo-controlled clinical trial. This means participants will be randomly allocated (and the participants and the doctors will not know what injection they are receiving) to receive weekly injections of either abatacept or placebo (dummy) treatment for a 12-month period. 

Treatment Period (Year 1): Participants will self-administer weekly injections for 12 months and will be seen every 3 months - their joints will be assessed for any sign of arthritis and bloods and urine tests will be taken.  Questionnaires will be completed by the participant.  An ultrasound of the joints will also be performed every six months (or earlier if it suspected RA has developed).  

Participants are asked to contact the team should there be any change in, or new, symptoms between their visits – especially joint swelling, at which point they will be seen promptly and re-assessed. 

If a participant does develop RA during the study, the study treatment is stopped and they are referred urgently to their local rheumatology team to begin the standard care of treatment for RA. 

Follow up (Year 2): Participants will now no longer take treatment but will still be seen every 3 months (or urgently if new symptoms develop) for similar assessments to those in year 1 to monitor if there is any sign of RA developing.

Were there any benefits or risks associated with taking part in this study?

We cannot predict the outcome, but there is the possibility that there will be benefits to those subjects receiving the active drug, including reduction of joint symptoms and effects on the disease process that may delay or even prevent the onset of RA.  

Another potential benefit to participating is that the participant may be monitored more closely by the clinical research team than they would usually be through the NHS. This means that if RA does develop at any point during the study there will be prompt assessment and management.

Additionally, although not of direct benefit to the participant, this study will provide important new information about the feasibility and acceptability of approaches to using treatment to prevent conditions such as RA.

 There are always risks associated with taking medication.  Subjects receiving active injection could potentially experience some of the following side effects:

Infections, headache, blood pressure increase, changes in liver function or white blood cell counts, diarrhoea, nausea, sore throat, fever, rashes, or injection site reactions in the skin.

In general, these are usually mild, and previous clinical trials of abatacept have shown that the medication is well tolerated in patients with early as well as established RA.  Nevertheless, participants are asked to report any adverse events so that these are managed promptly.